What is Lysodren®?

Lysodren® (Mitotane) is an adrenal cytotoxic active substance – an antineoplastic agent which suppresses production of adrenal cortex corticosteroid hormones. 1,2

Lysodren® role in ACC

Only FDA approved treatment for inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC) 1

WARNINGS: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA: In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock and discontinue LYSODREN until recovery.

How Lysodren® works

Research on the mode of action of mitotane suggests two main biological effects:

  • A direct cytotoxic effect on adrenal cortical cells, mediated through mitochondrial alterations and inhibition of sterol-O-acyl transferase 1 (SOAT1) 2
  • Inhibition of corticosteroid synthesis by modifying the peripheral metabolism of cortisol and directly suppressing the production of corticosteroids from the adrenal cortex 1,4

Management of advanced ACC not amenable to radical resection

Practice Guidelines on the management of adrenocortical carcinoma in adults5

ACC: adrenocortical carcinoma: EDP: etoposide, doxorubicin, cisplatin
Adapted from Fassnacht M, et al. Eur J Endocrinol.2018;179(4):G1-G46.

Reference notes from Practice Guidelines

  1. Only in selected patients (with severe hormone excess)
  2. The following factors might guide the decision: site of disease involvement, tumor burden, symptoms, tumor grade/Ki67 index
  3. The following factors might guide the decision: site of disease involvement, tumor burden, symptoms, tumor grade/Ki67 index, and importantly kinetics of tumor growth
  4. Radiotherapy, radiofrequency ablation, cryo-ablation, microwave ablation, (chemo-) embolization
  5. Few panellists favored cisplatin + etoposide
  6. Contact specialized center

Lysodren® dosing and monitoring the therapeutic window

Lysodren® is available as 500 mg tablets.1 The total daily dose should be divided into three or four doses.1

The recommended treatment schedule is to start the patient at 2-6 g dosing per day, in three to four divided doses. Doses can then be increased incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated.1

Time taken to reach target levels of Lysodren® and observe clinical benefits varies from patient to patient but typically requires a minimum of 4 months of continuous treatment.6

Finding and maintaining the Lysodren® therapeutic window

Optimal Plasma Concentration Target

Mitotane Plasma Level Monitoring is to be performed on a regular and individual basis to reach/maintain an optimal therapeutic window.6

REFERENCES

1. Lysodren® prescribing information, December 2020.
2. Waszut U, Szyszka P, Dworakowska D. Understanding mitotane mode of action, J Physiol Pharmacol 2017; 68 (1):13-26.
3. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma, N Engl J Med 2012; 366(23):2189-97.
4. Ghataore L, Chakraborti I, Aylwin S, et al. Effects of mitotane treatment on human steroid metabolism: implications for patient management, Endocr Connect 2012; 1(11):37-47.
5. Fassnacht M, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46.
6.
Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab. 2009;23(2):273-89.

Lysodren Adverse Events1

Most Common Adverse Effects

  • Anorexia, nausea, vomiting, and diarrhea (80%)
  • Depression, dizziness, or vertigo (15%-40%)
  • Rash (15%)
  • Neutropenia
  • Hepatitis, elevation of liver enzymes
  • Growth retardation, hypothyroidism
  • Confusion, headache, ataxia, mental impairment, weakness, dysarthria
  • Maculopathy
  • Hypercholesterolemia, hypertriglyceridemia
  • Decreased blood androstenedione and decreased blood testosterone in females, increased sex hormone binding globulin in females and males, decreased blood free testosterone in males
  • Gynecomastia

Less Common Adverse Effects

  • Hypertension
  • Orthostatic hypotension, flushing
  • Generalized aching, and fever
  • Visual blurring
  • Diplopia
  • Lens opacity, retinopathy
  • Prolonged bleeding time
  • Hematuria
  • Hemorrhagic cystitis
  • Albuminuria

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